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Caspase-8 regulation of TRAIL-mediated cell death

R N Crowder1, W S El-Deiry

  • 1Department of Medicine, Hematology/Oncology Division, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033 USA.

Experimental Oncology
|October 17, 2012
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise for cancer therapy by selectively killing malignant cells. However, resistance mechanisms, often involving caspase-8 dysfunction, limit its effectiveness.

Area of Science:

  • Molecular Biology
  • Cell Death Research
  • Cancer Therapeutics

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors are key regulators of apoptosis.
  • TRAIL exhibits selective toxicity towards tumor cells, making it a potential cancer therapy candidate.
  • Aberrant TRAIL signaling and resistance mechanisms in cancer cells can impede therapeutic efficacy.

Purpose of the Study:

  • To review the discovery and evolution of research on TRAIL and its receptors.
  • To elucidate the mechanisms underlying TRAIL resistance in cancer.
  • To highlight the central role of caspase-8 in TRAIL-mediated apoptosis.

Main Methods:

  • Comprehensive literature review of studies on TRAIL, TRAIL receptors, and caspase-8.
  • Analysis of reported mechanisms of TRAIL resistance.
  • Synthesis of findings related to caspase-8 expression, function, and mutations.

Main Results:

  • TRAIL-mediated tumor cell killing is a well-established phenomenon.
  • TRAIL resistance in cancer cells is frequently associated with impaired caspase-8 activity.
  • Mechanisms of caspase-8 dysfunction include mutations, epigenetic silencing, and altered stability.

Conclusions:

  • Understanding TRAIL and TRAIL receptor signaling is crucial for cancer therapy development.
  • Caspase-8 is a critical determinant of sensitivity to TRAIL-induced apoptosis.
  • Targeting caspase-8 pathways may overcome TRAIL resistance and enhance anti-cancer strategies.

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